This invention relates to use of dihydrolipoic acid (DHL) and a-lipoic acid to treat and prevent damage to the retina arising from physical forces such as exposure to laser beams, and to compositions containing phenyl nitrones and DHL or a-lipoic acid as neuroprotective agents.
The retina is part of the central nervous system and contains both neurons and glia, as well as photo receptors.
Although the immediate mechanisms vary, many forms of neuro-trauma are believed to share a common final pathway: the formation of neurotoxic free radicals.
Individuals experiencing laser-induced retinal trauma often report seeing a bright flash of light at the time of the incident and subsequently notice impaired vision. Impairment of vision is often noticed immediately and may be documented early. Retinal injuries may either improve or worsen over time. Clinically observed signs range from hemorrhage (vitreous, pre-, post- or intra-retinal) to whitening (burn) of the retina. In later stages, puckering and/or perforation of the retina may occur. In such cases, further deterioration occurs over time. For example, in one soldier suffering from bilateral exposure, visual acuity in one eye declined from 20/50 twenty four hours post-injury to 20/100 over 6 months, subsequently deteriorating further to 20/400. The clinical course of the other eye was quite different. While maintaining 20/20 visual acuity over 14 months, a paracentral scotoma enlarged significantly as color vision and contrast sensitivity declined progressively. Decrements in dark adaptation are also reported. Therapeutic interventions included administration of steroids to control edema and inflammation and surgical interventions to remove blood from the vitreous or to manage retinal detachment or perforations.
Clinical features of injury to the retina via laser or other physical means include hemorrhage. Just as intracranial hemorrhage may cause hemosiderosis in the brain, bleeding into the retina appears to cause deposition of iron and resultant toxicity. It appears that laser-induced coagulation of retinal blood vessels causes local areas of retinal ischemia and hypoxia. Laser energy may also directly disrupt and traumatize retinal neurons. Whether due to ischemia or to direct acoustic and thermal trauma caused by the laser energy, it is likely that glutamate would be released as with any type of neurotrauma.
Alpha-lipoic acid (xcex1LA) is an antioxidant currently used clinically to treat diabetic neuropathy. It has been shown to be clinically safe and was shown to be neuro-protective against ischemia-perfusion injury in both the rat and the gerbil. It was also effective against NMDA and malonic acid lesions of striatum in rats. However, its effects in preventing or ameliorating damage to the retina, especially damage arising from physical trauma such as laser-induced damage, has not previously been considered.
Nitrone-based free radical traps offer an ROS scavenging mechanism which differs from vitamin E and other endoge- nous compounds. The nitrones react covalently with ROS to form stable nitroxides and as such they differ from endogenous scavengers such as the lipoic acids. They have also been shown to be neuroprotective against glutamate-induced toxicity in cultured neurons as well as in several rodent models of cerebral ischemia. In the rat focal ischemia model, they are neuroprotective even when initiation of treatment was delayed. One such compound is xcex1-Phenyl-N-tert-butylnitrone (PBN), which crosses the blood brain barrier, but has been found to be somewhat toxic in high concentrations. PBN was reported to attenuate the accumulation of lactate following cortical contusion in the rat. In the rat focal ischemia model, PBN was neuroprotective even when initiation of treatment was delayed as long as 12 hours. PBN, as well as other nitrones, also minimized seizures and delayed time to death in mice subjected to intracerebral lethal injection of ferrous chloride. A newer nitrone, N-tert-Butyl-xcex1-[2-sulfophenyl]-nitrone (SPBN), is also an effective neuroprotectant. SPBN (500 ng by intraocular injection) has been shown to rescue 27% of retinal ganglion cells after axotomy (Klocker et al., J. Neurosci. 18(3):1038-1046). SPBN ( 100 mg/kg i.p. 30 min prior and q 8 hours for 48 hours after insult; or 300 mg/kg, ip, 1 hours prior to insult and 0,1,2,3,6,9,12,18 and 24 hours after)is protective against striatal injections of NMDA, kainic acid, AMPA, MPP+, 3-acetyl pyridine and malonate, decreasing the volume of the lesions induced by those toxins, as well as decreasing malonate-induced formation of ROS.
Azulenyl nitrones were shown to be protective against ischemic injury in the gerbil and against MTPT in mice. Finally, another nitrone, NXY-059, was shown to be effective in both temporary and permanent focal ischemia models in the rat and was effective when given 3 hours or even 5 hours after start of recirculation in the former. In preliminary studies, NXY-059, administered either 15 minutes prior or 30 minutes post traumatic brain injury, was effective in decreasing volume of necrosis in the controlled cortical impact mode.
This invention provides methods for preventing or ameliorating damage to the retina by administration of retinal protective/healing amounts of xcex1-lipoic acid or dihydrolipoic acid in appropriate pharmaceutical carriers. The active agents may be administered systemically or topically.
The invention also provides improved compositions containing lipoic acids, including analogues of the acids, in combination with nitrones chosen from xcex1-Phenyl-N- tert-butylnitrone (PBN) and N-tertButyl-xcex1-[2-sulfophenyl]nitrone (SPBN) which will provide synergistic effects when used in combination for preventing and/or ameliorating damage to neurological tissue.